PROJECT SUMMARY Children with sickle cell anemia (SCA) are at a significantly increased risk for deficits in multiple domains of cognitive functioning, including overall intelligence, executive function, verbal comprehension, and processing speed. The proposed study will examine the relations between the biological sequelae of SCA and performance on tests of cognitive function by leveraging access to participants in an ongoing NINDS R01 grant (R01 NS096127; PI: Jordan) testing a novel method of measuring oxygen extraction fraction (OEF) as a measure of recurrent stroke in children, adolescents, and young adults with SCA. Hemodynamic factors such as chronic anemia and cerebral blood flow velocity have been shown to be related to cognitive deficits in this population; however, no study has assessed cerebral OEF in relation to cognitive function. Further, studies have shown that problems with executive function and verbal comprehension skills in particular are associated with difficulties in coping with SCA-related stress, and deficits in these domains are associated with increased risk for emotional distress in this population and other pediatric and child populations as well. The proposed multimethod study will investigate the relations between hemodynamic characteristics (OEF, CBV, CBF) assessed with MRI methods, standardized assessment of cognitive and executive function (WISC-V, WAIS-IV, NIH Toolbox), and multi-informant reports on questionnaires of coping (RSQ-SC) and symptoms of anxiety and depression (CBCL, YSR, ASR). The primary aim is to examine cognitive function in participants with SCA and healthy controls in relation to a novel MRI-derived measure of OEF, after controlling for other measures of pathophysiology (i.e., cerebral blood volume, CBV; cerebral blood flow, CBF; and silent and overt strokes) and environmental factors (parental socioeconomic status; SES). It is hypothesized that lower scores on measures of cognitive function will be associated with higher OEF after controlling for other measures cerebral hemodynamics (CBV, CBF), incidence of stroke, and parental SES. Further, OEF will be a unique predictor of cognitive function for participants with SCA, but not for controls. The secondary aim examines psychosocial correlates (coping/emotion regulation and symptoms of anxiety and depression) of OEF and cognitive function. It is hypothesized that OEF will have a positive indirect association with symptoms of anxiety and depression, with cognitive functioning and coping/emotion regulation fully accounting for this association. Further, there will be a significant indirect association of OEF with symptoms of anxiety and depression for participants with SCA, but not for controls. Relations between biological characteristics and cognitive functioning/psychosocial outcomes will be prospectively examined. Training for the applicant will include new experiences with imaging methods, data management, and analyses, along with an opportunity to expand knowledge about the biological underpinnings of psychosocial functioning. Finally, this proposal will create new knowledge that addresses the gaps in the literature on cognitive functioning, coping, and distress in patients with SCA.